S100A9, also known as calgranulin B and myeloid related protein-14 (MRP-14), is a calcium- and zinc-binding protein that belongs to the S 100 protein family. S100A9 is highly expressed by the myeloid cell lineage and is found in the extracellular milieu during inflammatory conditions. S100A9 forms heterodimers with S100A8, another member of the S100 family. However, S100A9 may also form monomers which executes specific functions. Human S100A9 has a molecular mass of about 13 kDa and is composed of 114 amino acid residues.
The S100A8/A9 protein can bind to endothelium through the interaction of S100A9 with heparan sulphate proteoglycans or of the S100A8/A9 complex with carboxylated N-glycans exclusively expressed by endothelial cells after inflammatory activation. Another receptor that binds different S 100 proteins is the receptor for advanced glycation end products (RAGE). Direct binding to RAGE has so far been demonstrated for S100A12, S100B, S100A1, and S100P. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. RAGE consists of an extracellular domain, a single transmembrane spanning domain, and a highly charged cytosolic tail. RAGE signaling contributes to the activation of central cellular pathways which involve p38 or p44/42 MAP kinases, Cdc42/Rac, and NF-κB signaling components, thereby influencing features like cell survival, cell motility, and inflammatory response.
Binding of ligands to the RAGE receptor initiates cellular signals that activate NF-κB, which results in transcription of proinflammatory factors. The mammalian TOLL-like receptors (TLR) are receptors that recognize molecular patterns of pathogens. After the engagement of a pathogenic pattern ligand to TLR, recruitment of adaptor proteins, the transcription factor NF-κB is activated by the receptor-driven signaling cascade. It has been proposed that RAGE and TLR's use similar mechanisms which results in inflammatory reactions.